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. 2008 Nov;82(21):10756-67.
doi: 10.1128/JVI.00802-08. Epub 2008 Aug 13.

Noroviruses distinguish between type 1 and type 2 histo-blood group antigens for binding

Haruko Shirato  1 , Satoko Ogawa, Hiromi Ito, Takashi Sato, Akihiko Kameyama, Hisashi Narimatsu, Zheng Xiaofan, Tatsuo Miyamura, Takaji Wakita, Koji Ishii, Naokazu Takeda
Affiliations

Noroviruses distinguish between type 1 and type 2 histo-blood group antigens for binding

Haruko Shirato et al. J Virol. 2008 Nov.

Abstract

Norovirus (NoV) is a causative agent of acute gastroenteritis. NoV binds to histo-blood group antigens (HBGAs), namely, ABH antigens and Lewis (Le) antigens, in which type 1 and type 2 carbohydrate core structures constitute antigenically distinct variants. Norwalk virus, the prototype strain of norovirus, binds to the gastroduodenal junction, and this binding is correlated with the presence of H type 1 antigen but not with that of H type 2 antigen (S. Marionneau, N. Ruvoen, B. Le Moullac-Vaidye, M. Clement, A. Cailleau-Thomas, G. Ruiz-Palacois, P. Huang, X. Jiang, and J. Le Pendu, Gastroenterology 122:1967-1977, 2002). It has been unknown whether NoV distinguishes between the type 1 and type 2 chains of A and B antigens. In this study, we synthesized A type 1, A type 2, B type 1, and B type 2 pentasaccharides in vitro and examined the function of the core structures in the binding between NoV virus-like particles (VLPs) and HBGAs. The attachment of five genogroup I (GI) VLPs from 5 genotypes and 11 GII VLPs from 8 genotypes, GI/1, GI/2, GI/3, GI/4, GI/8, GII/1, GII/3, GII/4, GII/5, GII/6, GII/7, GII/12, and GII/14, to ABH and Le HBGAs was analyzed by enzyme-linked immunosorbent assay-based binding assays and Biacore analyses. GI/1, GI/2, GI/3, GI/4, GI/8, and GII/4 VLPs were more efficiently bound to A type 2 than A type 1, and GI/8 and GII/4 VLPs were more efficiently bound to B type 2 than B type 1, indicating that NoV VLPs distinguish between type 1 and type 2 carbohydrates. The dissociation of GII/4 VLPs from B type 1 was slower than that from B type 2 in the Biacore experiments; moreover, the binding to B type 1 was stronger than that to B type 2 in the ELISA experiments. These results indicated that the type 1 carbohydrates bind more tightly to NoV VLPs than the type 2 carbohydrates. This property may afford NoV tissue specificity. GII/4 is known to be a global epidemic genotype and binds to more HBGAs than other genotypes. This characteristic may be linked with the worldwide transmission of GII/4 strains. GI/2, GI/3, GI/4, GI/8, GII/4, and GII/7 VLPs bound to Le(a) expressed by nonsecretors, suggesting that NoV can infect individuals regardless of secretor phenotype. Overall, our results indicated that HBGAs are important factors in determining tissue specificity and the risk of transmission.

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Figures

FIG. 1.
FIG. 1.
Diagram of carbohydrate structures used in this study. Monovalent carbohydrate-biotin reagents (A) were synthesized and used in the experiments shown in Fig. 5 and 6, and multivalent carbohydrate-biotin reagents (B) were used in the experiments shown in Fig. 4. Glc, glucose; Fuc, fucose; Gal, galactose; GlcNAc, N-acetylglucosamine; Lac, lactose; GalNAc, N-acetylgalactosamine; R1, biotin; R2, polyacrylamide with biotin.
FIG. 2.
FIG. 2.
Dose-dependent binding of GI/1 r124 (A to E) or GII/1 rHV (F) to saliva. Serially twofold-diluted saliva samples, at 50- to 102,400-fold dilution, were used to coat the microplates. Convalescent-phase serum from a patient infected with the GI/2 258 strain and r258 were used for the internal standard. Coating buffer was used for the blank. The binding of the VLPs was detected by using polyclonal rabbit anti-VLPs as described in Materials and Methods.
FIG. 3.
FIG. 3.
Binding between VLPs and saliva samples. The saliva samples were tested at a dilution of 1:1,600. The binding of the VLPs was detected by polyclonal rabbit anti-VLPs as described in Materials and Methods. The experiments were performed in triplicate and reproduced at least twice. Each data point represents the mean value (with error bar).
FIG. 4.
FIG. 4.
Binding between VLPs and synthetic histo-blood group carbohydrates. The multivalent carbohydrate-biotin reagents conjugated to polyacrylamide were tested at a concentration of 2.5 μg/ml. H type 1 trisaccharides and r124 were used for the internal standard. Tris-buffered saline was used for the blank. The binding of the VLPs was detected by polyclonal rabbit anti-VLPs as described in Materials and Methods. The experiments were performed in duplicate and reproduced at least twice. Each data point represents the mean value (with error bar).
FIG. 5.
FIG. 5.
Interaction between NoV and synthetic histo-blood group carbohydrates. The monovalent carbohydrate-biotin reagents were captured on a streptavidin-coated sensor chip as described in Materials and Methods. Sensorgrams show the binding of the VLPs to immobilized carbohydrates, H type 1 and type 2 (A to F), A type 1 and type 2 (G to L), or B type 1 and type 2 (M to R). At 180 s, 40 μ1 of the VLP was injected at a flow rate of 20 μl/min and was replaced by the running buffer at 300 s. The binding curves of 180 to 300 s showed the association, whereas those of 300 to 500 s showed the dissociation. The binding curves between VLPs and two different carbohydrates were compared by overlaying the sensorgrams obtained on each surface. The experiments were reproduced at least twice. The y axis indicates the resonance signal as shown in resonance units (RU).
FIG. 6.
FIG. 6.
Dose-dependent binding of GII/4 r104 to the monovalent carbohydrate-biotin reagents. Serially twofold-diluted carbohydrate-biotin reagents, at 1.0 to 0.016 pmol/μl, were used to coat streptavidin-precoated plates. Tris-buffered saline was used for the blank. The binding of the VLPs was detected by polyclonal rabbit anti-VLPs as described in Materials and Methods. The optical densities at 492 nm are plotted against the dilutions.
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